The discovery of the antiviral APOBEC3 (A3) proteins is regarded as one of the most therapeutically promising breakthroughs in HIV/AIDS molecular virology in the last decade. Several A3 proteins have the capacity to restrict HIV replication by incorporating into assembling viral particles, physically interfering with the progression of reverse transcription, and deaminating viral cDNA cytosines to uracils. The latter antiviral activity is the defining hallmark of A3-mediated restriction, explaining the genomic strand G-to-A mutations that are frequently observed in patient-derived viral sequences. Here, we will address two major questions. First, we will ask whether stable A3H haplotypes provide a barrier to HIV acquisition in instances where the transmitting virus originates from a person with an unstable A3H haplotype. Moreover, in individuals where the virus overcomes this barrier and transmission still occurs, we also ask how the virus adapts to efficiently counteract stable A3H and how this relates to disease progression. These experiments are motivated by preliminary data showing that stable A3H haplotypes potently restrict the replication of viruses with naturally occurring hypofunctional vif alleles. These studies have the potential to explain why some highly exposed individuals naturally resist viral infection. Second, we will ask whether HIV has additional mechanisms, independent of Vif, to counteract restriction by A3 proteins. This will be addressed through a series of vif-null virus adaptation experiments to restrictive pressures imposed by A3 proteins, followed by comprehensive analyses of the resulting mutations to deduce the underlying escape mechanisms. These experiments are anticipated to provide genetic portals into aspects of the restriction mechanism that are poorly understood such as A3 post-translational regulation, assembly, packaging, and encapsidation. Together, our studies on transmission could have immediate clinical implications, and our studies on Vif-independent resistance will provide novel mechanistic insights and have longer-term clinical implications as the field moves further toward the development of therapeutics such as Vif inhibitors that will be able to leverage this powerful innate immune defense system to block HIV replication and pathogenesis.